Characterization of an alternatively spliced GADD45a GADD45a1 isoform in arsenic-treated epithelial cells

A new GADD45a isoform, GADD45a1, was identified in the cellular response to arsenic. DNA sequencing and biochemical analyses suggested that GADD45a1 is derived from an alternative splicing of the GADD45a mRNA by skipping the region corresponding to exon2 of the gadd45a gene during mRNA maturation. In addition to the size difference due to the lack of 34 amino acids encoded by exon2, GADD45a1 and GADD45a proteins differ in their effects on cell proliferation and cell cycle transition. Unlike GADD45a, the GADD45a1 is unable to attenuate cell growth. In over-expression experiments, the full length GADD45a, but not the GADD45a1, sensitized cells to arsenic- induced prometaphase arrest of the cell cycle. Furthermore, GADD45a1 appears to be able to antagonize the function of the GADD45a on the G2/M phase cell cycle arrest as demonstrated in cotransfection experiment. Thus, these data suggest that the generation of the GADD45a1 isoform may not only offset but also antagonize the effects of arsenic and GADD45a on cell growth and cell cycle regulation.